Histamines are representative chemical mediators that induce allergic reactions, and the histamines are released from cells such as mast cells and basophils when substances that are causative of allergy are entered into the body. The released histamines are bound to a histamine type 1 receptor (H1 receptor) protein to exhibit pharmacological actions such as hypotension, vascular hyperpermeability, constriction of smooth muscles, vasodilatation, or glandular hypersecretion, and involved in the manifestation of allergic reactions and inflammations. As described above, histamines are related to various diseases of human, and the allergic diseases and inflammations can be prevented or cured by controlling their actions. Agents for controlling histamine release and agents for inhibiting the binding of histamines with receptors (antihistamines) are numerously commercially available, and the agents are used in diseases such as bronchial asthma, allergic rhinitis, pollinosis, urticaria, and atopic dermatitis.
However, antihistamines that are conventionally known exhibit some undesired side effects such as sedative action, drowsiness, dizziness, and malaise, based on the actions on the central nervous system; and dry mouth, mucosal dryness, and visual impairment, based on the anti-cholinergic actions; therefore, there are some limitations of use such as prohibition of taking antihistamines before driving automobiles, which in turn cause inconvenience in use. For these reasons, antihistamines which are free from such problems and have excellent effects are in demand from the patients and the medical sites. The present inventors have found a piperidine derivative of the present invention having smaller side effects of the central nervous system and potent antihistamine action.
Piperidine derivatives having a thiabenzo azulene backbone are disclosed in Patent Publications 1 to 13, among which those that are disclosed in Patent Publications 1 to 7 are compounds that are different from the compound of the present invention, in that both of R1 and R2 in the following general formula (I) are a hydrogen. In addition, Patent Publication 8 discloses a compound where R1 in the following general formula (I) is an alkyl which may be substituted by an acyl or a hydroxy, and R2 is a hydrogen or a chlorine. Patent Publications 9 to 13 disclose compounds where R1 is a hydrogen, and R2 is a halogen, an alkyl, or an alkoxy in the following general formula (I). However, Patent Publication 8 discloses that the compound has sedative action, and Patent Publication 9 discloses that a compound has antagonistic actions for ptosis and catalepsy, and suppressive actions for abnormal drop in body temperature and tremors, respectively. In addition, the compounds disclosed in Patent Publications 10 to 13 are described to possess antihistamine action, but do not disclose on the amelioration on the side effects on the central nervous system, such as drowsiness, which is a side reaction of conventional antihistamines, as in the compounds of the present invention. For example, ketotifen fumarate disclosed in Patent Publication 10 is widely used as a second generation antihistamine, it is a matter to be remarked upon use on the side reactions that induced drowsiness. As described above, no reports have been so far made on piperidine derivatives having a thiabenzo azulene backbone having smaller side effects on the central nervous system and potent antihistamine actions as in the compounds of the present invention.    Patent Publication 1: Japanese Patent Laid-Open No. Hei-3-294277    Patent Publication 2: Japanese Unexamined Patent Publication No. 2001-519789    Patent Publication 3: Japanese Unexamined Patent Publication No. Hei-6-504992    Patent Publication 4: Japanese Patent Laid-Open No. Hei-1-104069    Patent Publication 5: Japanese Patent Laid-Open No. Sho-57-77673    Patent Publication 6: Japanese Examined Patent Publication No. Sho-57-60351    Patent Publication 7: Japanese Unexamined Patent Publication No. Hei-3-504855    Patent Publication 8: Japanese Patent Laid-Open No. Sho-49-69677    Patent Publication 9: Japanese Patent Laid-Open No. Sho-51-110572    Patent Publication 10: Japanese Examined Patent Publication No. Sho-52-17030    Patent Publication 11: Japanese Examined Patent Publication No. Sho-55-8984    Patent Publication 12: Japanese Patent Laid-Open No. Sho-48-81869    Patent Publication 13: French Patent No. 1,437,412